Title Non-Invasive Biomarkers for Diagnosing Clinically Significant Prostate Cancer Project Summary/Abstract Despite the indolent natural history of many newly diagnosed prostate cancers (PC), most men still undergo primary curative therapy with associated side effects and costs, i.e. overtreatment. There is an clear need for the development and implementation of new management strategies for localized PC which would be enhanced if founded upon accurate assessments of disease status and the potential for indolent versus aggressive behavior. This proposal will test the hypothesis that biomarkers indicative of adverse PC characteristics (e.g. high Gleason pattern) can be reproducibly detected in the urine of men with PC. We further hypothesize that initial sampling of a panel of noninvasive urine biomarkers and the repeated evaluation of these markers over time will associate with the presence of significant versus insignificant cancer in the prostate, and thus can be used in informing decisions for surveillance or proceeding with definitive treatment. The- se hypotheses will be tested through specific aims designed to exploit distinct prostate cancer-associated RNAs using quantitative urine assays and a multi-institutional longitu- dinal cohort of men managed by active surveillance with attendant biospecimens, patho- logical, and clinical data. The successful completion of these aims will provide non-invasive tools for the initial and longitudinal assessment of prostate cancers in order to inform accurate treatment decisions for localized disease.